This proposal is designed to expand the scope of the Sharpless aminohydroxylation "AA', toward the synthesis of novel nucleoside and isonucleoside analogs. This powerful reaction has shortened the synthesis of beta-hydroxyamine groups from a multi-step synthesis to a single step. The possible nitrogen sources and olefin substrates for this transformation will be extended through our work and may lead to a concise, combinatorial method for the synthesis of unusual nucleoside templates. Nucleosides represent an important class of molecules that have undergone clinical trials and shown good efficacy against a variety of tumors for leukemia, breast and lung cancers. A number of these, Cladribine, Cytarabine Ocfosfate and Gemcitabine, have recently been approved by the FDA for clinical use. Using the Sharpless AA, we will attempt to generate a library of nucleo- and isonucleoside derivatives which can be quickly purified and submitted to the National Cancer institute for the 60 cell line screen. One of the limiting factors in drug discovery has been the facile and rapid synthesis of large numbers of drug candidates; we will attempt to alleviate this through our use of a template-directed combinatorial synthesis.